title: Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.
abstract: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Wijsman
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Pankratz
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Choi
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Rothstein
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Faber
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Arrastia
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Martin
authors.initials: M
authors.lastname: Farlow
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sweet
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D000067878:CELF Proteins; D016022:Case-Control Studies; D051152:Clusterin / Q000235:genetics*; D005190:Family; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011157:Population Dynamics; D025341:Principal Component Analysis; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; C101410:BIN1 protein, human; D000067878:CELF Proteins; C117363:CELF2 protein, human; C495242:CLU protein, human; D051152:Clusterin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins